ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.6005G>A (p.Arg2002His) (rs768326843)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521615 SCV000617995 likely pathogenic not provided 2017-08-17 criteria provided, single submitter clinical testing The R2002H variant in the COL7A1 gene has been reported previously, in trans with a nonsense variant, in a patient with epidermolysis bullosa (Takeichi et al. 2015). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2002H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at the Y residue in the Gly-X-Y triple helical region that is conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same codon (R2002C) and nearby Glycine residues (G2003R, G2003E, G2006A, G2006D) have been reported in the Human Gene Mutation Database in association with dystrophic epidermolysis bullosa (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R2002H as a likely pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV001195226 SCV001365533 uncertain significance not specified 2020-01-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg2002His variant in COL7A1 has been reported in one individual with recessive dystrophic epidermolysis bullosa (RDEB) who was compound heterozygous for a second truncating variant in COL7A1 (Takeichi 2015). It has also been identified in 0.004% (1/23998) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. And, although this variant falls in the triple helical region of the collagen molecule, it is in the Y position of a Gly-X-Y repeat and most disease-associated variants in this region are Gly substitutions (Dang 2008). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3.
Natera, Inc. RCV001272349 SCV001454261 likely pathogenic Epidermolysis bullosa dystrophica inversa, autosomal recessive 2020-09-16 no assertion criteria provided clinical testing

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